RASA1-driven cellular export of collagen IV is required for the development of lymphovenous and venous valves in mice
RASA1-driven cellular export of collagen IV is required for the development of lymphovenous and venous valves in mice
复制标题
DOI：
10.1242/dev.192351
复制
发表时间：
2020-12-01
期刊：
影响因子：
4.6
通讯作者：
King, Philip D.
中科院分区：
文献类型：
--
作者：
Chen, Di;Geng, Xin;King, Philip D.
RASA1是RAS-MAPK信号的负调控因子，在淋巴管瓣的发育和维持中起着至关重要的作用。然而，淋巴静脉瓣膜(LVV)和静脉瓣膜(VV)的发育和维持是否需要RASA1尚不清楚。在这项研究中，我们表明，在小鼠胚胎中诱导Rasal的破坏并不影响LVV或中心VV的初始规格，但确实影响了它们的继续发育。同样，转而表达一种催化失活形式的RASA1会导致LVV和VV发育受损。LVV发育受阻与形成LVV的内皮细胞(EC)中基底膜蛋白IV型胶原的积聚有关，MAPK抑制剂和促进IV型胶原折叠的药物可以部分或完全挽救LVV的形成。在成年小鼠中，阻断Rasal会导致静脉高压和VV功能受损，这与VV小叶上的EC丢失有关。综上所述，RASA1在EC中作为RAS信号的负性调节因子，是EC输出IV型胶原所必需的，从而允许LVV的发展和VV的发展和维持。
RASA1, a negative regulator of Ras-MAPK signaling, is essential for the development and maintenance of lymphatic vessel valves. However, whether RASA1 is required for the development and maintenance of lymphovenous valves (LVV) and venous valves (VV) is unknown. In this study, we show that induced disruption of Rasal in mouse embryos did not affect initial specification of LVV or central VV, but did affect their continued development. Similarly, a switch to expression of a catalytically inactive form of RASA1 resulted in impaired LVV and VV development. Blocked development of LVV was associated with accumulation of the basement membrane protein, collagen IV, in LVV-forming endothelial cells (EC), and could be partially or completely rescued by MAPK inhibitors and drugs that promote collagen IV folding. Disruption of Rasal in adult mice resulted in venous hypertension and impaired VV function that was associated with loss of EC from VV leaflets. In conclusion, RASA1 functions as a negative regulator of Ras signaling in EC that is necessary for EC export of collagen IV, thus permitting the development of LVV and the development and maintenance of VV.